Our research is aimed at an elucidation of the biochemical structure of membrane sites that are involved in the control of ion permeability in nerve and muscle. Reactive groups of membrane proteins and lipids will be chemically modified by reagents of known specificities. Resultant effects on excitation will be quantitated by a series of electrophysiological and pharmacological techniques. In this way, residues associated with individual aspects of excitation will be identified, and their role characterized. Radioactive analogs of the reagents used for chemical modification are potentially useful as labels for further biochemical analysis, and several methods are proposed for increasing the specificity of labeling to components of interest. Our most recent work involves the use of reagents known to possess a high degree of specificity for sulfhydryl groups. These compounds have been found to selectively alter a particular aspect of the gating of sodium channels in neurons. Our goal in this work is to obtain information that may lead to a better understanding of the mechanism of action of neuropharmacological agents and ultimately allow the rational design of drugs, including anesthetics, with high specificity. BIBLIOGRAPHIC REFERENCES: Jaimovich, E., R.A. Venosa, P. Shrager and P. Horowicz. 1976. Density and distribution of tetrodotoxin receptors in normal and detubulated frog sartorius muscle. J. Gen. Physiol. 67: 399-416. Shrager, P. 1976. 'Slow' inactivation of sodium conductance in nerve following reaction with N-ethylmaleimide. Biophys. J. 16: 75a.